BR122022026476B1 - METHOD FOR LOADING NESTED PHARMACEUTICAL CONTAINERS WITH A FLUID PHARMACEUTICAL SUBSTANCE - Google Patents

Abstract

The system of the invention involves monitoring and controlling in a sterilizable environment the peeling of a cover from a vat sealed by the cover. The system and associated method employ a platform having a fiducial source locating structure for retaining the tub, a cover removal station arranged to engage with the cover, and to peel the cover from the tub. The container assembly for holding nested pharmaceutical container parts comprises a bottom, an upper rim that provides a horizontal upper sealing surface that has a peripheral contour, and side walls located between the bottom and the upper rim, a peelable container cover that consists of a sheet of flexible material sealed to the sealing surface of the upper edge of the rectangular container to seal the contents of the container and a cover removal accessory on the container cover.

Description

Background of the invention Field of invention

[001] This present invention relates to the medical field as exemplified in IPC class A61 and more particularly to the apparatus and associated methods for sterilization, and sterile handling, of pharmaceutical materials and containers for pharmaceutical products, which include placing pharmaceutical products in the form for administration to veterinary or medical patients. In one aspect, it refers to the programmed and automatic operation of such apparatus.

Background

[002] The matter of loading pharmaceutical products into pharmaceutical containers is a main aspect of the pharmaceutical industry. The matter is highly controlled by various government entities and officials in several countries. Technologically, the matter is a challenge since pharmaceutical products need to be loaded into containers under very strict aseptic conditions. Very specific procedures are specified for this task to a degree that makes handling pharmaceuticals profoundly different from handling any other industrial product, including specifically semiconductors, which also demand extreme and consistent environmental conditions. In fact, the parallels between handling semiconductors in semiconductor “clean labs” and handling pharmaceuticals in aseptic isolators are superficial. They share the use of such “clean laboratories”, however, there is no inherent aseptic requirement associated with semiconductor manufacturing.

[003] Loading pharmaceutical containers with fluid pharmaceutical products specifically requires aseptic handling of both the containers and the pharmaceutical fluid itself. This results in complex mechanisms and procedures, several of which may be automatic to one degree or another. Sometimes the production equipment for handling pharmaceutical fluid is large and expensive. This creates a problem for smaller operations, particularly in small-scale production and development environments. As the field developed, the need for smaller, more compact equipment, particularly in the loading and compounding of fluid pharmaceuticals, became evident.

[004] The prior art is typically characterized by the use of vibrating bowls and exhausts. Several prior art systems also employ the use of gloves by the operator to access the interior of the chamber.

Summary of the invention

[005] In a general aspect, the invention presents a method for loading nested pharmaceutical containers with a pharmaceutical fluid substance, such as a liquid, solution or suspension that has therapeutic properties. The method includes providing a loading system that comprises a sterilizable chamber that is capable of maintaining an aseptic condition, wherein the chamber comprises a loading station and a flat rotary stage that has a target fiducial location structure that includes restriction surfaces. . The method also includes transferring into the chamber at least one container well sealed by a container well cover and containing a container nest supporting a plurality of pharmaceutical containers, aseptically sealing the chamber, and establishing an aseptic condition within the chamber. The container nest supporting the plurality of pharmaceutical containers is transferred to the target fiducial location structure such that the container nest is held in place by the restraining surfaces and the pharmaceutical fluid substance is distributed into at least a portion of the plurality of pharmaceutical containers operating both the rotary stage and the loading station.

[006] In some embodiments, operation of the charging station may include rotating the charging station. Dispensing the pharmaceutical fluid substance may comprise dispensing the pharmaceutical fluid substance on an iterative and serial basis into the containers. Providing a loading system may comprise providing a loading apparatus comprising at least one cover removal station within the chamber, wherein transferring to the target fiducial location structure the container nest comprises removing the container well cover from the container vat operating both the rotating stage and at least one cover removal station. Operating the at least one cover removal station may comprise rotating the at least one cover removal station. Providing the loading system may comprise providing within the chamber at least one cover removal station having a coupling tool, transferring to the chamber at least one container bowl may comprise attaching to the container bowl cover a container bowl cover. cover and operating the at least one cover removal station may comprise engaging the engagement tool with the cover removal accessory.

[007] The method may further comprise transferring into the chamber a container closure bowl sealed by a container closure bowl cover and containing at least one container closure nest that supports a plurality of pharmaceutical container closures. The method may further comprise positioning one of the nests of at least one closure to align closures in the at least one closure nest with corresponding containers in the container nest, transferring the nests of closures and aligned containers to the pressing station by rotating it. se the rotary stage and force closures on the corresponding containers. Positioning one of the at least one closure nest may comprise obtaining image information about the one of the at least one closure nest, and positioning the one of the at least one closure nest based on the image information.

[008] Positioning one of the at least one closure nest may comprise applying a vacuum to the suction cups, lifting the container closure nest with the suction cups and operating the rotary stage. Transferring the container nest to the target fiducial location opening may comprise applying a vacuum to the suction cups, lifting the container nest with the suction cups, and operating the rotary stage. Dispensing the pharmaceutical fluid substance may comprise simultaneously and/or serially operating the rotary stage and the loading station, and removing the container vessel cover may comprise simultaneously and/or serially operating the rotary stage and at least one removal station. of coverage.

[009] In another general aspect, the invention presents a system for loading nested pharmaceutical containers with a pharmaceutical fluid substance that comprises a sterilizable chamber that is capable of maintaining an aseptic condition. The chamber includes a loading station and a flat rotary stage having a geometric axis of rotation of the rotary stage and comprising a target fiducial location structure that includes restraining surfaces arranged and shaped to receive and retain a pharmaceutical container nest that supports a plurality of pharmaceutical containers.

[0010] In additional embodiments, the charging station may comprise a fluid product distributor head, wherein the charging station is configured to be rotatable about a charging station axis of rotation parallel to the geometric axis of rotation. of the rotary stage to position, in combination with rotation of the rotary stage, the dispenser head over any one of the plurality of pharmaceutical containers retained in the container nest in the target fiducial location structure. The chamber may additionally comprise at least one cap removal station and the rotary stage may further comprise a first source fiducial locating structure that includes restriction surfaces arranged and shaped to receive and retain a source closure bowl. pharmaceutical container sealed by a container closure bowl cover and containing at least one pharmaceutical container closure nest that supports a plurality of pharmaceutical container closures and at least one second source fiducial location opening arranged and shaped to receive and retaining a pharmaceutical container well sealed by a container well cover and containing a pharmaceutical container nest that supports a plurality of pharmaceutical containers.

[0011] The at least one cover removal station may be arranged and configured to be rotatable about a cover removal station rotation axis parallel to the rotational axis of the rotary stage for removing, in combination with the rotation of the rotary stage, the container vat cover of the at least one container vat and the container closure vat cover of the container closure vat. At least one cover removal station may comprise a coupling tool arranged and configured to engage with coupling accessories pre-attached to the container bowl cover and the container closure bowl cover.

[0012] The system may further comprise at least one camera arranged to obtain image information about at least one of the container nest and the closure nest, and a controller, wherein the camera additionally comprises at least one control system. vacuum collection comprising suction cups arranged to engage with the container nests and the container closure nests, wherein the at least one vacuum collection system is configured, in combination with rotation of the rotary stage, to lift a pharmaceutical container nest of a pharmaceutical container vat retained in one of at least one second source fiducial location opening and for depositing the pharmaceutical container nest in the target fiducial location opening in combination with rotation of the rotary stage and for lifting a pharmaceutical container closure nest of a pharmaceutical container closure vat retained in the first source fiducial location opening and for depositing the container closure nest onto the pharmaceutical container nest under control of the controller.

[0013] The controller may be operative to instruct at least one camera to provide the controller with image information and the controller may be operative to control the rotation of the rotary stage to place closures in the closure nest in correspondence with containers in the nest. of container. The system may further comprise a pressing system configured to force closures on corresponding containers.

[0014] The system may additionally comprise at least one rotating cover removal station having a cover removal station rotation axis parallel to the rotational stage rotation axis, at least one vacuum collection system for placing the container closure nest in the container nest with closures in the closure nest in correspondence with containers in the container nest, and a pressing system for forcing the closures into the containers, wherein the loading station is a loading station rotary stage having a charging station rotation axis parallel to the rotational stage rotation axis and comprising a fluid product distributor head. The system may further comprise at least one camera for obtaining image information from at least one of the container nest and the closure nest, and a controller comprising a memory and a processor. The controller may be operative to instruct the rotary stage to rotate to angular positions that are one of predetermined and based on image information and to control the at least one cover removal station, the charging station, the at least one system. vacuum collection and pressing system to operate in conjunction with the rotary stage.

[0015] In a further general aspect, the invention features a system for loading nested pharmaceutical containers with a pharmaceutical fluid substance that includes means for establishing and maintaining an aseptic condition in a chamber, means for restraining a container nest that supports a plurality of pharmaceutical containers in the chamber and means for transferring a container nest to the means for restricting a container trough in the chamber. It also includes means for rotating the means for restricting the chamber; and means for distributing the pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers in the container nest while the container nest is restrained by the means for restricting.

[0016] In a further aspect, a system is provided for loading nested pharmaceutical containers with a pharmaceutical fluid substance, the system comprising a sterilizable chamber that is capable of maintaining an aseptic condition, wherein the chamber comprises: a flat rotary stage having an axis of rotation of the rotary stage, a plurality of locating structures positioned with respect to the rotatory stage at different positions around the geometric axis of rotation of the rotatory stage, for retaining nests of pharmaceutical container parts at different positions around of the geometric axis of rotation of the rotating stage and a container loading station having a dispensing head for loading the containers while they are retained in a nest in one of the locating structures. The locating structures may include surfaces associated with a first bowl-retaining opening in the rotary stage for retaining a first bowl containing at least one nest of containers, surfaces associated with a second bowl-retaining opening in the rotary stage for retaining a second vat containing at least one nest of closures and surfaces associated with a target nest-retaining opening in the rotary stage for retaining at least one nest.

[0017] The chamber may additionally comprise at least one vacuum collection system comprising suction cups arranged to engage with the container nest and container closure nest retained in the rotary stage, the at least one collection system being Vacuum collection is configured in combination with rotation of the rotary stage to lift a pharmaceutical container nest from a pharmaceutical container vat and to deposit the pharmaceutical container nest into the target opening in combination with rotation of the rotary stage and to lift a pharmaceutical container closure nest of a pharmaceutical container closure vat and for depositing the container closure nest onto the pharmaceutical container nest.

[0018] At least one of the locating structures may include a reconfigurable locating structure with one or more adjustable positioning surfaces for positioning a vat with respect to the rotating stage. The reconfigurable locating structure may include at least one pair of a reconfigurable stopping member and a restraining member disposed opposite each other through an opening in the rotary stage to precisely position in a first predetermined position a tub containing at least one nest. The stopping member may be adjustable to stop the bowl in the first predetermined position through a rotational adjustment and the restraining member may be arranged to restrain the bowl in the first predetermined position.

[0019] At least one of the first reconfigurable location structures may include a rotary positioning element that has a geometric axis of rotation parallel to a plane of the rotary stage and includes a plurality of different positioning surfaces that are selectable by rotating the rotary positioning element. At least one of the reconfigurable location structures may include a pair of opposing rotary positioning elements, each of which has a geometric axis of rotation parallel to a plane of the rotary stage and each may include a plurality of different positioning surfaces that are selectable by rotating the rotary positioning elements to accommodate different nest widths.

[0020] At least one of the reconfigurable location structures may include at least a first pair of opposing positioning elements that define opposing positioning surfaces along a first positioning geometric axis that is at least generally parallel to a plane of the rotary stage and at least a second pair of opposing positioning elements defining opposing positioning surfaces along a second geometric positioning axis that is at least generally parallel to a plane of the rotary stage and at least generally perpendicular to the first geometric positioning axis. The at least one of the positioning elements in each of the first and second pairs of positioning elements may include a rotary positioning element that has a geometric axis of rotation parallel to a plane of the rotary stage and includes a plurality of mounting surfaces. different positioning.

[0021] The system may additionally include a reconfigurable vacuum collection system comprising: a first set of suction cups arranged in a first pattern, a second set of suction cups arranged in a second pattern different from the first pattern, and a selection mechanism operative for positioning the first set of suction cups or the second set of suction cups to engage with the at least one first of the nests of pharmaceutical container parts while being retained by one of the plurality of locating structures . The selection mechanism of the reconfigurable vacuum collection system may include a rotary mechanism operative to position the first or second sets of suction cups in an engaging position.

[0022] The system may additionally include at least one cover removal station positioned to remove covers from vats containing at least one nest of pharmaceutical packaging materials retained in one of the locating structures. The at least one cover removal station may be rotatable about an axis of rotation of the cover removal station parallel to the geometric axis of rotation of the rotary stage to remove the vat covers in combination with rotation of the rotary stage. The at least one cover removal station may comprise a coupling tool arranged and configured to engage with a cover removal accessory on the tub cover.

[0023] The charging station may be configured to be rotatable about a charging station rotation axis parallel to the rotating stage rotation axis to position, in combination with rotation of the rotating stage, the distributor head on any one of the plurality of pharmaceutical containers held by one of the locating structures.

[0024] The system may further comprise at least one camera arranged to obtain image information about at least one of the nests of pharmaceutical container parts. The system may further comprise a pressing system configured to force nested closures on corresponding nested containers.

[0025] The system may additionally comprise at least one rotating cover removal station having a cover removal station rotation axis parallel to the rotational stage rotation axis, at least one vacuum collection system to place a container closure nest in a container nest with closures in the closure nest in correspondence with containers in the container nest; a pressing system to force closures on containers; and wherein the charging station is a rotary charging station having a charging station rotation axis parallel to the rotational stage rotation axis and comprising a fluid product distributor head.

[0026] The system may further comprise at least one camera for obtaining image information from at least one of the container nest and the closure nest, a controller comprising a memory and a processor, and wherein the controller is operative to instruct the rotary stage to rotate to angular positions that are one of predetermined and based on image information and to control the at least one cover removal station, the loading station, the at least one vacuum collection system and the pressing system to operate in conjunction with the rotary stage.

[0027] In another aspect, a system is provided for loading nested pharmaceutical containers with a pharmaceutical fluid substance comprising: means for establishing and maintaining an aseptic condition in a chamber; means for restraining a container nest supporting a plurality of pharmaceutical containers in the chamber; means for transferring to means for restricting a container nest from a container trough in the chamber; means for rotating the means for restricting in the chamber; and means for distributing the pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers in the container nest while the container nest is restrained by the means for restricting.

[0028] In a further aspect, a method is provided for loading nested pharmaceutical containers with a pharmaceutical fluid substance, the method comprising: providing a loading system comprising a sterilizable chamber that is capable of maintaining an aseptic condition, wherein the chamber comprises a charging station and a flat rotating stage having a target location structure; transferring into the chamber at least one container well sealed by a container well cover and containing a container nest supporting a plurality of pharmaceutical containers; aseptically seal the chamber; establish an aseptic condition within the chamber; transferring to the target location structure the container nest supporting the plurality of pharmaceutical containers, such that the container nest is held in place; and distributing the pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers by operating both the rotary stage and the loading station. Operation of the charging station may include rotating the charging station. Dispensing the pharmaceutical fluid substance may comprise dispensing the pharmaceutical fluid substance on an iterative and serial basis into the containers.

[0029] Providing a loading system may comprise providing a loading apparatus comprising at least one cover removal station within the chamber and wherein transferring to the target location structure the container tub comprises removing the cover from container vat of the container vat operating both the rotary stage and at least one cover removal station. Operating the at least one cover removal station may comprise rotating the at least one cover removal station. Providing the loading system may comprise providing within the chamber at least one cover removal station having a coupling tool, wherein transferring into the chamber at least one container bowl may comprise attaching to the container bowl cover an accessory. covering removal; and wherein operating the at least one cover removal station comprises engaging the engagement tool with the cover removal accessory.

[0030] The method may further comprise transferring into the chamber a container closure bowl sealed by a container closure bowl cover and containing at least one container closure nest that supports a plurality of pharmaceutical container closures. The method may further comprise positioning one of the nests of the at least one closure to align closures in the at least one closure nest with corresponding containers in the container nest; transferring the nests of closures and aligned containers to the pressing station by rotating the rotary stage; and force closures on the corresponding containers. The method may further include adjusting a vat locating structure to accommodate a size of the enclosing nest vat. Positioning one of the at least one closure nest may comprise: obtaining image information about one of the nests of the at least one closure; and positioning the one of the nests of at least one closure based on the image information. Positioning one of the at least one closure nest may comprise: applying a vacuum to the suction cups; lift the container closure nest with the suction cups; and operate the rotary stage.

[0031] Transferring the container nest to the target location opening may comprise: applying a vacuum to the suction cups; lift the container nest with the suction cups; and operate the rotary stage. The method may further include selecting one of a plurality of sets of suction cups and wherein applying a vacuum to the suction cups is performed for the selected set of suction cups. Selection may include rotating one of a plurality of sets of suction cups into position. The method may additionally include target location structure to accommodate a size of the container nest. Adjustment can be carried out in two at least generally orthogonal directions. The method may further include adjusting a tub locating structure to accommodate a size of the container nest tub.

[0032] In another general aspect, the invention features a container assembly for holding nested pharmaceutical container parts. It includes a container comprising a bottom, an upper rim providing a horizontal upper sealing surface having a peripheral contour, and side walls located between the bottom and the upper rim. It also includes a peelable container cover consisting of a sheet of flexible material sealed to the sealing surface of the upper edge of the rectangular container to seal the contents of the container and a cover removal accessory on the container cover.

[0033] The sealed peelable container cover may include a portion extending outward from the peripheral contour of the upper sealing surface of the container and the cover removal accessory may be on the portion of the peelable container cover extending outward from the peripheral contour of the upper sealing surface of the container. The container may be rectangular and includes four side walls. The cover removal accessory may include an attachment to allow it to be engaged by a coupling tool. The cover removal accessory may include a ball-shaped attachment to allow it to be engaged by a coupling tool. The peelable container cover may be heat sealed to the upper rim sealing surface of the rectangular container to seal the contents of the container against decontamination. The peelable container cover may be sealed to the sealing surface of the upper rim of the rectangular container to seal the contents of the container against decontamination with the use of a chemical agent. The peelable container cover may be sealed to the sealing surface of the upper edge of the rectangular container to seal the contents of the container against decontamination using a radiation. The peelable container cover may be sealed to the sealing surface of the upper rim of the rectangular container to seal the contents of the container against decontamination using plasma. The peelable cover can be produced from a plastic material. Peelable roofing can be produced from a waterproof laminated metal sheet. The peelable covering can be produced from a polymeric membrane. The cover removal accessory may be attached to a portion of the peelable container cover that extends outside the peripheral contour of the upper sealing surface of the container. The sealed container may retain sterile pharmaceutical closures or containers.

[0034] In a further aspect, there is provided a method for removing in a controlled environment enclosure a container cover from a sealed container, wherein the sealed container is sealed by the container cover, wherein the method comprises: providing the container in the controlled environment housing of the sealed cover to a sealing surface of a rim of the container to seal the contents of the container against decontamination, wherein the cover has a cover removal attachment, decontaminate the sealed container in the controlled environment housing, engage the cover removal accessory with a coupling tool, and remove the cover from the container using the coupling tool. The hitch can engage the cover removal accessory with a fork-shaped hitch tool. The hitch can engage a ball-shaped attachment to the cover removal accessory.

[0035] Supply may include providing sterilized pharmaceutical containers or closures in the sealed container prior to decontamination. Securing may occur before the container is in the controlled environment enclosure. Decontamination of the container sealed in the controlled environment enclosure may occur prior to removal of the cover. Removing the cover may include moving the engagement tool relative to the container. Removing the cover may include moving both the container and the coupling tool. The method may further comprise attaching the cover removal accessory to the cover prior to providing the container in the controlled environment enclosure.

[0036] In a further aspect, a method is provided for removing in a sterilizable environment a cover from a vat sealed with the cover, wherein the method comprises: providing a sterilizable chamber that is capable of maintaining an aseptic condition; retaining in the chamber a sealed vat with a detachable cover, wherein the vat and cover have corresponding pluralities of corners; illuminating one or more peeling monitoring zones near the decoating station with light from at least one light source; peel off the cover from one of the plurality of corners of the tub; measuring a first light intensity of illumination in one of the peeling monitoring zones proximate to and not substantially overlapping the vat and after at least a portion of the peeling; assess the current situation of the tank cover peeling based on the first light intensity; and provide an indication of the current assessed situation. Measuring a first light intensity may comprise measuring a first light intensity of the diffusely reflected light source from one of the peel monitoring zones.

[0037] The method may further comprise deciding a next step in the removal process based on the current peeling situation. Evaluating a current situation of peeling of the cover of one of the plurality of corners of the bowl may comprise comparing the first light intensity with a first predetermined light intensity value. Assessing a current situation of the peeling of the cover of one of the plurality of corners of the tub may comprise detecting the cover that blocks light from the lighting in one of the peeling monitoring zones.

[0038] The method may further comprise, if one of the plurality of corners of the bowl is the last of the plurality of corners to be peeled, detaching the cover completely from the bowl; measuring a final light intensity of illumination in one of the peeling monitoring zones; and evaluate the detachment of the tank cover based on the last light intensity and the first light intensity. Assessment of the detachment of the bowl cover may comprise comparing the last light intensity with a predetermined last light intensity value. Measuring the ultimate light intensity may comprise measuring light from the diffusely reflected light source from one of the peel monitoring zones.

[0039] The peeling monitoring zones may be on a movable platform and peeling the cover of one of the plurality of corners of the tub may comprise moving the platform. Providing the sterilizable chamber may comprise providing a sterilizable chamber comprising a rotating stage plane having a source locating structure for effecting retention of the vessel, and peeling off the cover of one of the plurality of corners of the vessel may comprise rotating the rotational internship plan. Providing the sterilizable chamber may comprise providing a movable platform having a source locating structure for holding the tub, and peeling off the cover from one of the plurality of corners of the tub may comprise moving the platform.

[0040] Providing the chamber may comprise providing a cover removal station comprising a hooking tool and peeling may comprise: attaching a removable cover accessory to the cover bowl before placing the bowl on the source locating structure; engage the removable cover accessory with the coupling tool; and move the coupling tool. Providing the sterilizable chamber may comprise providing a sterilizable chamber comprising a rotating stage plane having a source locating structure for effecting retention of the vessel, and peeling off the cover of one of the plurality of corners of the vessel may comprise rotating the rotational internship plan.

[0041] In a further aspect, a system is provided for automatically monitoring and controlling the removal in a sterilizable environment of a sealed cover for a vat, wherein the vat and cover have corresponding pluralities of corners, wherein the system comprises: a sterilizable chamber having the capacity to maintain an aseptic condition, wherein the chamber comprises: a source locating structure arranged to retain the tub in a fixed position, a cover removal station arranged to engage with the cover and peel off the cover of the vat, a peel monitoring surface positioned proximate to the coating removal station, one or more light sources arranged to illuminate at least that portion of the peel monitoring surface, and one or more light sensors sensitive to light from the source of light and arranged to preferably collect and measure diffusely reflected light from the illuminated portion of the peel monitoring surface. The system may further comprise a controller in communication with the covering removal station, the light source and the light sensor. The light source may be an infrared light source and the sensor may be an infrared sensor.

[0042] The controller may comprise a memory and software instructions that when loaded into memory and executed by the controller cause the controller to operate the cover removal station, the light source and the light sensor. The peel monitoring surface may be part of a surface of a mobile platform; and software instructions when loaded into memory and executed by the controller may additionally cause the controller to have the ability to move the platform. The moving platform may be a rotating stage plane having a geometric axis of rotation of the rotating stage. At least one of the cover removal station and the platform may be operable to peel the cover from one of the plurality of corners of the tub and move a peeled portion of the cover into a peel monitoring zone, wherein the monitoring zone is within the illuminated portion of the platform, close to the vat and not substantially overlapping the vat.

[0043] The sensor may be configurable to measure a first light intensity of the diffusely reflected light source from the peel monitoring zone; and the software instructions when loaded into memory and executed by the controller may additionally allow the controller to: operate at least one of the light sources and at least one of the sensors to measure the first light intensity immediately following the peeled portion the cover has been moved to the peeling monitoring zone; assess the current situation of the tank cover peeling based on the first light intensity; and determine a next step in removal based on the current peeling situation. A first predetermined light intensity value may be stored in memory and software instructions when loaded into memory and executed by the controller may additionally allow the controller to evaluate a current pot cover peeling situation by comparing the first intensity. of light with the first predetermined light intensity value.

[0044] If the first of a plurality of corners of the bowl is the last of the plurality of corners that are peeled, the software instructions when loaded into memory and executed by the controller may additionally allow the controller to: operate at least one of the cover removal station and the platform to detach the cover completely from the tub; operating at least one of the light sources and at least one of the sensors to measure an ultimate light intensity of the diffusely reflected light source from the peeling monitoring zone; and evaluate the detachment of the tank cover based on the last light intensity and the first light intensity. A last predetermined light intensity value can be stored in memory; and the software instructions when loaded into memory and executed by the controller may additionally allow the controller to evaluate the unattachment of the bowl cover by comparing the last light intensity to the last predetermined light intensity value.

[0045] Systems and methods, according to the invention, do not need to employ vibrating basins or exhausts. Neither such systems or method require gloves. Systems and methods according to the invention can therefore address the need for compaction, small-scale loading and compounding of fluid pharmaceutical products.

Brief description of the drawings

[0046] The features and objects of the present invention mentioned above, among others, and the manner of achieving the same will become more apparent and the invention itself will be better understood by means of reference to the following description of an embodiment of the invention taken into account combination with the accompanying drawings, in which: Figure 1A is a drawing of an apparatus for loading pharmaceutical containers with a pharmaceutical fluid product. For clarity, some surfaces are shown in cropped form and others are shown as transparent.

[0047] Figure 1B is a plan view of a chamber of the apparatus of Figure 1A.

[0048] Figure 1C shows a rotating stage of the apparatus of Figure 1A and Figure 1B.

[0049] Figure 1D shows a side view of a portion of the apparatus of Figure 1A and Figure 1B.

[0050] Figure 1E shows a pharmaceutical container tub cover resting on the rotating stage of Figure 1A to Figure 1D that is removed.

[0051] Figure 1F shows pharmaceutical containers that are loaded with a pharmaceutical fluid substance in the apparatus of Figure 1A to Figure 1E.

[0052] Figure 1G provides a more detailed view of the cover removal components of the apparatus of Figure 1A, Figure 1B and Figure 1E.

[0053] Figure 2A and Figure 2B together form a drawing of a flowchart for a method of aseptically loading pharmaceutical containers with a pharmaceutical fluid substance in a spatially restricted environment.

[0054] Figure 3A is a subsystem drawing of another embodiment of an apparatus for loading pharmaceutical containers with a pharmaceutical fluid product.

[0055] Figure 3B shows a portion of Figure 3A in greater detail.

[0056] Figure 4A is a subsystem drawing of a further embodiment of an apparatus for loading pharmaceutical containers with a pharmaceutical fluid product.

[0057] Figure 4B shows a portion of Figure 4A in greater detail.

[0058] Figure 5A is a subsystem drawing of yet a further embodiment of an apparatus for loading pharmaceutical containers with a pharmaceutical fluid product.

[0059] Figure 5B shows a portion of Figure 5A in greater detail.

[0060] Figure 6 shows a flowchart of an additional method for loading nested pharmaceutical containers with a pharmaceutical fluid substance.

[0061] Figure 7 is a drawing of the apparatus of Figure 1A to 1G additionally equipped with a light source and an additional sensor.

[0062] Figure 8A to 8D is a set of drawings showing the peeling in the system of Figure 7 of a cover of a vat sealed by the cover in conjunction with the use of the light source and additional sensor to monitor and control the peeling of coverage.

[0063] Figure 9 shows a flowchart that provides greater details of the peeling step of the flowchart in Figure 2A as performed using the system of Figure 7 and Figure 8A to 8D.

[0064] Corresponding reference characters indicate corresponding parts throughout the various views. Although the drawings represent embodiments of the present invention, the drawings are not necessarily to scale and certain features may be exaggerated to better illustrate and explain the present invention. Flowcharts are also representative in nature, and actual embodiments of the invention may include additional features or steps not shown in the drawings. The exemplifications presented in this document illustrate embodiments of the invention, in one or more forms, and such exemplifications should not be interpreted as limiting the scope of the invention in any way.

Detailed Description

[0065] The embodiments disclosed below are illustrative and are not intended to be exhaustive or limit the invention to the precise form disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can utilize their teachings.

[0066] The present invention relates to an apparatus and method for loading pharmaceutical containers with a pharmaceutical fluid substance in a spatially restricted environment. In Figure 1A, the loading system 1000 comprises a sealable chamber 100 in communication with an environment, wherein the sealable chamber 100 has the ability to have an aseptic environment established within it and the ability to maintain such an aseptic environment within its interior. The interior of the sealable chamber 100 may be rendered aseptic by any one or more of a variety of treatments, including, but not limited to, treatment with a sterilant, such as water vapor, hydrogen peroxide vapor, ozone, nitrogen dioxide. and ethylene oxide. The structures and mechanisms for carrying out such sterilization steps are well known in the art and are not shown in Figure 1A.

[0067] Chambers 200 and 300 are separated from chamber 100 by upper wall 110 and lower wall 120 respectively, and are not required to have the capacity to maintain aseptic environments within their interiors. Communication of the chamber 100 with the environment may be via a suitable aseptically sealable access port 102, schematically shown in dotted outline in Figure 1A. Suitable sealable entrances and doors are well known in the art and will be discussed later in this specification. The environment could be, for example, a clean room adapted for handling pharmaceutical products during production. Since space is important in such spatially restricted clean environments, there is much greater merit in reducing the so-called “identification” of equipment to be housed in the clean environment.

[0068] The terms “aseptic” and “sterilize” and their derivatives should be understood as follows for the purposes of this specific report. Establishing an aseptic condition within a chamber should be understood to mean establishing such a condition throughout the entire internal atmosphere of the chamber as well as on substantially all exposed interior surfaces of the chamber. This shall include the surfaces of all items, containers, subsystems and the like exposed to the chamber's interior atmosphere. To the extent that extremely tight gaps or microscopic gaps may exist within the chamber, so that a sterilizing gas or vapor may not perfectly penetrate such tight regions, for example, the degree of sterilization in practical cases may not be complete. This is recognized both within the industry and in the standards set for the industry. The action of establishing an aseptic condition within the interior of the chamber and “sterilizing the interior of the chamber” shall have the same meaning in this report as described.

[0069] The introduction into a chamber with an aseptic condition of an item whose surfaces are not adequately sterilized destroys the aseptic condition existing within the chamber. On the other hand, the introduction of an aseptic or sterilized item into an interior of a chamber that does not have an aseptic condition within such interior does not render such interior aseptic. In fact, what this does is destroy the aseptic condition of the surface of the item thus introduced. Similarly, introducing filtered air, even with all biological entities filtered out, into a non-sterilized chamber in no way sterilizes the chamber or makes it aseptic to a degree acceptable in the pharmaceutical industry. The reason is that the interior surfaces of the chamber are not sterilized by the introduction of such air. What is achieved is contamination of the filtered air with active biological species residing on the interior surfaces of the non-sterilized chamber.

[0070] For the purpose of clarification and completeness, it should also be noted that in the art the term “aseptic” is sometimes also used in association with the introduction of pharmaceutical fluids along aseptic tubes into bodies within controlled chambers. In such cases, the term in the art refers to the condition within the tube or the fact that the pharmaceutical fluid can be filtered to an adequate degree. This in no way sterilizes or makes the interior of the chamber in question aseptic. The aseptic condition in such cases is confined to the interior of the tube carrying the pharmaceutical stream. Such streams are often filtered to a high degree, but such filtration only affects the interior of the particular tube and in no way sterilizes the interior of the chamber.

[0071] In some prior art systems, containers introduced into a chamber for the purposes of being loaded with a pharmaceutical product are guided through sterilization subsystems. This eliminates biological species in the containers. When such sterilized containers are introduced into the chamber and the chamber itself is not aseptic, the containers lose their aseptic conditions since biological species contained within the chamber will be deposited in the previously aseptic containers.

[0072] It should be noted that pharmaceutical or semiconductor cleanrooms of any quality level, including “Class 100”, “Class 10” or “Class 1”, even when employing laminar flow hoods and the like or any quality of HEPA (High Efficiency Particulate Air) or ULPA (Ultra Low Particulate Air) filters do not constitute an aseptic chamber due to the fact that they do not have an assured means of making the surfaces of the aseptic chamber sterile or aseptic. Standards for cleanrooms exist from both the United States Federal Government and ISO (International Organization for Standardization). These specify in greater detail the different standards of the allowable particulate content of a cubic volume of air in such a cleanroom installation. None of these standards address the issue of biological species present on surfaces in the cleanroom. This is to consider that a chamber cannot be made aseptic by managing its atmosphere or airflow alone. Nor, on the other hand, can the chamber be made aseptic by sterilizing only the surfaces inside it.

[0073] The text “Guideline for Disinfection and Sterilization in healthcare Facilities, 2008” by Rutala et al. from the Center for Disease Control lists a compendium of mechanisms and methods for sterilization. The concern in this particular report is specifically with such mechanisms for sterilizing the interior of a chamber; that is, sterilize both the interior surfaces and the atmosphere within the chamber. With the requirements determined, steam-based methods are best suited to the task. These include, but are not limited to, treatment with heated water vapor, hydrogen peroxide vapor, ozone, nitrogen dioxide, ethylene oxide, glutaraldehyde vapor or other suitable sterilizing gases and vapors. In a suitable method suitable for the present invention, sterilization is carried out by means of hydrogen peroxide vapor which is then discharged using ozone before the chamber is employed in loading pharmaceutical containers.

[0074] The subsystems of the apparatus 1000 contained in the sealable chamber 100 will now be described from Figure 1A to Figure 1G. Due to the compactness and density of components and subsystems of apparatus 1000, certain components and subsystems are omitted from the drawings of Figure 1B to Figure 1G for clarity and focus is placed on the components and subsystems most relevant to the supporting text in this specification. . The planar rotary stage 130 is completely rotatable through 360 degrees in a horizontal plane parallel to the bottom wall 120 about the axis of rotation of the rotary stage 131 and can be raised and lowered by means of the through feed of bellows 190. The use of feed Bellows traverse 190 allows the chamber 100 to retain its aseptic condition during movement of the rotary stage 130. A suitable motor and gear system 320 may be housed within the chamber 300. Motors, e.g., stepper motors, as well as Suitable gear systems for rotating the rotary stage 130 with adequate angular accuracy and repeatability are well known in the art and are not further discussed in this specification.

[0075] As shown in Figure 1C, at least three fiducial locating openings 132, 134, and 136 are provided in the rotary stage 130. Fiducial locating opening 132 is employed to receive container vats 530 that hold pre-sterilized pharmaceutical containers 510 packaged in a predetermined pattern in nests of containers 500. Container vats 530 are typically substantially rectangular and are sealed with peelable covers 520. Suppliers of pharmaceutical containers provide their product in this format to users of the apparatus of this specific report. Fiducial locating opening 134 is employed to receive container closure vats 630 that retain prepackaged sterile pharmaceutical container closures 610 in a predetermined pattern in container closure nests 600. Container closure vats 630 are typically rectangular substantially and are sealed with peelable pot covers not shown in Figure 1A to Figure 1G. Peel-off vessel covers 630 are functionally identical to peel-off covers 520. Pharmaceutical container suppliers provide their product in this format to users of the apparatus of this specific report. In the interest of compactness of the system 1000, the rectangular axes of locating openings 132, 134, and 136 may be oriented at an angle with respect to the radial direction of the rotating stage 130 in order to ensure a suitably small radius for rotating stage 130.

[0076] Suitable container nests 500 and container closure nests 600; the container vats 530 and the container closure vats 630; and peelable tub covers 520 are described in Patent Application published in U.S.2016-0200461, the specific report of which is incorporated in its entirety herein. Cover handle arrangements for removing bowl covers from pots are also described in U.S. Patent Application Published No. 2016-0251206, the specific report of which is incorporated in its entirety herein.

[0077] For the purpose of clarity, Figure 1A to Figure 1G show, and the associated text to be followed below will describe, the use of single bowl 530 of pharmaceutical containers 510 in conjunction with single bowl 630 of container closures 610. In practice, container closures 610 are provided as multiple nests 600 per bowl of container closure 630. For this purpose, the rotary stage 130 may contain more than one fiducial location opening 132 so that each receives a respective one from one bowl. of container 530 that holds prepackaged sterilized pharmaceutical containers 510 in container nest 500. In still other implementations, more than one nest 500 of containers 510 may be present in a single pharmaceutical container vat 530.

[0078] The fiducial location opening 136 is specifically arranged to receive container nests 500 that carry pharmaceutical containers 510. While the vats 530 and 630 are naturally located in the fiducial location openings 132 and 134 and are suspended by their own hoops since are in opening 132 and 134, the containers 510 are correctly located in opening 136 and retained in position by some other mechanism. For this purpose, the fiducial location opening 136 comprises four fiducial retention tabs 137. The base plate 138 is located within the fiducial location opening 136 as a loose component of the system 1000, and rests on horizontal portions on the bottom portions of each of four fiducial retention tabs 137 (see Figure 1C and Figure 1D). This arrangement allows the base plate 138 to move freely, guided by fiducial retention guides 137. This arrangement should be returned to when discussing the closure of containers with container closures.

[0079] Figure 1E shows the fiducial location opening 136 as empty, while the cover 520 is peeled away from the container trough 530 at the fiducial location opening 132 (not visible) to expose the nest 500 which carries pharmaceutical containers 510. At this point In operation of the system 1000, a cover similar to cover 520 has already been peeled off from the bowl 630 at the fiducial location opening 134 (not visible) to expose the nest 600 carrying container closures 610. Figure 1G shows an enlarged detailed view of the peeling of the cover 520. The cover removal station 140 is rotatable about the axis of rotation of the cover removal station 144 parallel to the axis of rotation of the rotary stage 131 and comprises engagement tool 142, which, in this particular embodiment, is fork-shaped in order to engage with the cover removal accessory 540 attached to the cover 520. The cover removal accessory 540 is pre-attached to the cover 520 before the bowl 530 is transferred to the system 1000 by means of input 102 (See Figure 1A). In the embodiment shown in Figure 1E and Figure 1G, the cover removal accessory 540 is clipped to the cover 520 and has a ball-shaped attachment to allow it to be engaged by coupling tool 142. Other combinations of cover removal accessories cover and coupling tools are contemplated and the system 1000 is not limited to the particular combination of cover removal accessory and coupling tool shown in Figure 1A, Figure 1E and Figure 1G. Cover removal accessory 540, for example, may be manufactured as an integral part of cover 520 for use in loading systems, such as loading system 1000. Or it may be stapled to cover 520 during placement in the vat. 530 of nests 500 carrying containers 530 and during placement in the vat 630 of nests 600 carrying container closures 610.

[0080] The rotary stage 130 can be lowered to assist in obtaining a less acute angle between the cover 520 and the bowl 530. Too sharp an angle can result in the cover 520 tearing. The cover removal station 140 can be rotated while the rotary stage 130 rotates, such that the combined movements of cover removal station 140 and rotary stage 130 provide a low stress path for removing cover 520, thereby limiting the chances of cover tearing 520. In In particular, the cover removal station 140 may be rotated to ensure that the engagement tool 142 is not present above the fiducial location opening 132 when the container bowl 530 is placed in or removed from the fiducial location opening 132.

[0081] In some embodiments, the system 1000 comprises a single cover removal station 140 for sequentially removing the covers from the vats 520 and 620. In other embodiments, the system 1000 may be equipped with two or more cover removal stations 140 for dedicated removal of covers from vats 520 and 620 and other additional vats. In some embodiments, the covers are simultaneously removed from the vats 520 and 620 and other vats, wherein all removal processes benefit from a single rotational movement of the rotary stage 130.

[0082] In Figure 1A, Figure 1B and Figure 1F, the charging station 170 for loading pharmaceutical containers 510 with pharmaceutical fluid product comprises pharmaceutical fluid product supply line 172 that supplies the pharmaceutical fluid product to a dispenser head. pharmaceutical fluid product 174 (See Figure 1F). The charging station 170 is rotatable about the axis of rotation of the charging station 176 parallel to the axis of rotation of the rotating stage 131. The charging station 170 and the rotating stage 130 may simultaneously or sequentially rotate to place the head of dispenser 174 over an opening of any selected container 510 in nest 500 when nest 500 is resting in fiducial location opening 136. This allows all containers 510 in nest 500 to be loaded with pharmaceutical fluid product by product dispenser head 174. When not engaged with loading containers 510, the loading station 170 can be rotated to swing the dispensing head 174 completely in the opposite direction to the fiducial location opening 136, thereby allowing nests 600 that carry container closures 610 are placed over the nest 500 with closure 610 directly over an opening of all containers 510 residing in the fiducial location opening 136.

[0083] Another term used to describe the dispenser head 174 is “loading needle”. Suitable charging needles and protective sheath arrangements for such charging needles are described in Patent Applications No. 2016-0346777 and U.S. 2017-0121046, the specifications of which are incorporated in their entireties herein.

[0084] Figure 1A and Figure 1B show two vacuum capture systems 150 and 160, each respectively comprising a plurality of suction cups 152 and 162 (See Figure 1B). The vacuum capture system 150 is arranged to capture nests 500 from containers 510 by means of suction cups 152, and the vacuum capture system 160 is arranged to capture nests 600 from containers 610 by means of suction cups 162. The vacuum capture system 160 may be raised and lowered to allow the suction cups 162 to engage with different nests 600 of container closures 610 contained at different depths within the bowl 630. For this purpose, the vacuum capture system 160 Vacuum 160 may comprise a bellows through feed that allows vertical movement while maintaining the aseptic integrity of chamber 100. Suitable vacuum pumps, or vacuum lines from a vacuum source external to system 1000, may be connected to the capture systems at vacuum 150 and 160, and ensure adequate vacuum for suction cups 152 and 162.

[0085] Cameras 210 and 220 are arranged to view and record the positioning of suction cups 152 and 162 in nests 500 and 600, respectively. In the embodiment shown in Figure 1A, cameras 210 and 220 are arranged within chamber 200 and viewed in nests 500 and 600 through sealed windows 112 and 122, respectively. In other embodiments, cameras 210 and 220 may be disposed within chamber 100 and viewed in nests directly from within chamber 100.

[0086] The container closure pressing system 180, shown in Figure 1A, Figure 1B and Figure 1D, comprises an upper pressing plate 182 disposed within the chamber 100 above the rotary stage 130, the lower pressing plate 184 arranged within the chamber 100 below the rotary stage 130, and the pressing unit 310 within the chamber 300. The pressing unit 310 is arranged to drive the lower pressing plate 184 vertically towards the upper pressing plate 182 by means of through feed. of bellows 186. The base plate 138 released from the fiducial location opening 136, when located above the lower pressing plate 184 by suitably rotating the rotary stage 130, is pushed upward by pressing plate 184 and is guided in the process by the fiducial retention tabs 137 (See Figure 1D). When the closures 610 in the closure nest 600 are ultimately pushed against the upper pressing plate 182, they are forced into the openings of the containers 510 in the nest 500. This creates a sandwiched nest of enclosed containers 510, in which each one is terminated by a corresponding closure 610. As shown in Figure 1D, nests 500 and 600 are forced together in the process to create a composite nest 500/600.

[0087] Controller 400, shown in Figure 1A and Figure 1B, may communicate with the remainder of system 1000 via control communications line 410, or may be physically contained within system 1000, e.g., within the chamber 200. The controller 400 may have suitable memory and a processor that contains suitable software programming instructions that, when loaded into memory and executed by the processor, control the movements of the pressing system 180, the vertical movement and the rotational action of the rotary stage. 130, the application of vacuum to vacuum capture systems 150 and 160, the imaging by cameras 210 and 220, the vertical movement of vacuum capture system 160, any rotational or vertical movements required from the cover removal stations 140 and charging station 170, as well as the on and off valve for supplying pharmaceutical fluid product to dispenser head 174. Suitable valves and pumps, typically peristaltic pumps, required for supplying pharmaceutical fluid product to dispenser head 174 are are well known in the art and may be housed in chamber 200 or may be located outside of system 1000. The various mechanical units for the subsystems described above that are well known in the art will not be discussed in detail here. These may typically be housed in the chamber 200 of the system 1000. The software, when executed by the processor, instructs the rotary stage to rotate to angular positions that are predetermined or based on image information from the cameras and removal station controls. cover, charging station, vacuum capture systems and pressing system to operate specifically in conjunction with the rotating stage.

[0088] A method based on system 1000 for loading nested pharmaceutical containers with a pharmaceutical fluid product will now be described by means of the flowchart determined in Figure 2A, and which is continued in Figure 2B. The method comprises providing [2010] loading apparatus 1000 comprising sterilizable chamber 100 capable of maintaining an aseptic condition, wherein the chamber comprises rotary stage 130 with target fiducial location opening 136 and at least two source fiducial location openings (132 and 134); charging station 170; at least one cover removal station 140; vertically oriented container pressing system 180; and at least one vacuum capture system (e.g. 150 and/or 160). The method further comprises transferring [2020] to at least one first of the at least two source fiducial location openings (132 and 134) at least one container well 530 sealed by the container well cover 520 and containing container nest 500 carrying a plurality of pharmaceutical containers 510; and transferring [2025] to a second of the at least two source fiducial location openings (134 and 132) the container closure bowl 630 sealed by a closure bowl cover and containing at least one nest of container closures 600 carrying a plurality of pharmaceutical container closures 610.

[0089] The method further comprises aseptically sealing [2030] the chamber 100 and establishing [2035] an aseptic condition within the chamber 100. Establishing [2035] an aseptic condition within the chamber 100 may comprise treating the interior of the chamber 100 with any of one or more of water vapor, hydrogen peroxide vapor, ozone, nitrogen dioxide, and ethylene oxide.

[0090] The method further comprises operating [2040] the at least one cover removal station 140 and rotating the rotary stage 130 to remove the container bowl cover 520 from the at least one container bowl 530 and removing the bowl cover closure of the closure vat 630; operate [2050] the rotary stage 130 and one of at least one vacuum capture system (e.g., 150 and/or 160) to transfer to the target fiducial location opening 136 the container nest 500 carrying the plurality of pharmaceutical containers 510; and dispensing [2060] in an iterative and serial manner a pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers 510 by operating the rotary stage 130 and the loading station 170. The phrase “iterative and serial” is employed in this specification to describe the fact that the same operative steps are repeatedly used to load the various containers and the fact that the containers are loaded one after the other, as opposed to simultaneously. In some embodiments, multiple containers may be simultaneously loaded using a loading station with multiple dispenser heads.

[0091] Steps [2040], [2050] and [2060] each involve rotating the rotary stage 130 and operating another device, which is, respectively, the cover removal station 140, one of at least one vacuum capture system (e.g. 150 and/or 160) and the charging station 170. The movements involved may be simultaneous in some cases or embodiments, and in series in other cases or embodiments. In some embodiments, part of the movements may be simultaneous and others may be in series.

[0092] Operation [2040] of the at least one cover removal station 140 may comprise engaging a coupling tool (e.g., tool 142) with a cover removal accessory (e.g., accessory 540) pre-attached to the cover that is removed. Operating [2050] one of the at least one vacuum capture system may comprise placing the container nest 500 in contact with a plurality of suction cups 152 while applying a vacuum to the suction cups 152. Dispensing [2060] a substance pharmaceutical fluid in at least a portion of the plurality of pharmaceutical containers may comprise iteratively and serially disposing the fluid product dispensing head 174 of the charging station 170 over the openings of the at least a portion of the plurality of pharmaceutical containers 510. Operation [2050] of the rotary stage 130 and one of the at least one vacuum capture system may comprise operating the camera 210 to obtain image information from container nest 500 carrying the plurality of pharmaceutical containers 510 and to position the one of at least one vacuum capture system over the container nest 500.

[0093] The method further comprises operating [2070] one of at least one vacuum capture system (e.g. 150 and/or 160) and the rotary stage 130 to transfer to the target fiducial location opening 136 one of the at least one container closure nest 600 carrying the plurality of pharmaceutical container closures 610 and positioning the at least one closure nest 600 to align closures 610 with containers 510; operating [2080] the rotary stage 130 to position together the aligned container nest 500 and the closure nest 600 in the pressing system 180; and operating [2090] the pressing system 180 to force the plurality of container closures 610 onto the plurality of containers 510.

[0094] Operating [2070] one of the at least one vacuum capture system may comprise placing the nest of container closures 600 in contact with a plurality of suction cups 162 while applying a vacuum to the suction cups 162. Operating [2090] ] the pressing system 180 may comprise driving the plurality of pharmaceutical containers 510 toward the upper pressing plate 182 of the pressing system 180.

[0095] Operating [2070] the rotary stage 130 and one of the at least one vacuum capture system may comprise operating camera 220 to obtain image information from the one of the at least one container closure nest 600 carrying the plurality of pharmaceutical container closures 610 and for positioning the one of the at least one vacuum capture system over the one of the at least one container closure nest 600.

[0096] Providing [2010] a charging apparatus may comprise providing a charging apparatus that further comprises the controller 400 and a software program executable by the controller 400. Any one or more of aseptically sealing [2030] the chambers 1000; establishing [2035] an aseptic condition within the chamber 100; operate rotary stage 130; operating at least one cover removal station 140; operating [2070] one of at least one vacuum capture system (150 and/or 160); operate charging station 170; and operating [2090] the pressing system 180 can be performed automatically by running the software program on the controller.

[0097] In the embodiment described by means of Figures 1A to 1F, in which each of the steps [2040], [2050], [2060], [2070] and [2080] comprises rotating a rotating stage, for example, the stage rotary 130, which carries container nests and container closure nests.

[0098] In other embodiments a plurality of steps of removing a container bowl cover from at least one container bowl 530; removing a container bowl cover from at least one container closure bowl 630; transferring to the destination fiducial location opening 136 the container nest 500; dispensing a pharmaceutical fluid substance into pharmaceutical containers 510; transferring to destination fiducial location opening 136 one of at least one container closure nest 600; and positioning the aligned container nest 500 and the closure nest 600 in the pressing system 180 comprises rotating a rotary stage that carries the container nests and container closure nests.

[0099] In a general embodiment, at least one of the steps of removing a container bowl cover from at least one container bowl 530; removing a container bowl cover from at least one container closure bowl 630; transferring to the destination fiducial location opening 136 the container nest 500; dispensing a pharmaceutical fluid substance into pharmaceutical containers 510; transferring to destination fiducial location opening 136 one of at least one container closure nest 600; and positioning the aligned container nest 500 and the closure nest 600 in the pressing system 180 comprises rotating a rotary stage that carries the container nests and container closure nests.

[00100] It should be noted that neither the charging system 1000 nor the associated method need employ the vibrating bowls or exhausts that are typical of the prior art. Unlike many prior art systems, the loading system 1000 also does not require the use of gloves for use by the operator to access the interior of the chamber.

[00101] The above system has been described as employing a controller that executes execution stored software on a general purpose computer platform, but can also be deployed in whole or in part using special purpose hardware.

[00102] The system described above also employs defined fiducial openings at the rotary stage to retain the vats and nests, but may also employ other types of fiducial structures that include other configurations of restraining surfaces sufficient to retain the vats and nests in place. . Notched posts mounted on the rotating stage can retain vats and/or nests above the rotating stage, for example. Additional location fiducial structures for retaining nest tubs for containers or container closures will be described in Figures 3A, 3B, 4A and 5A.

[00103] As shown in Figure 7 and Figures 8A to 8D, charging system 1000 may comprise peel monitoring sensor 230 arranged to collect light from a source fiducial location aperture, e.g., 132 or 134, when the fiducial location opening 132 or 134 is located proximate the cover removal station 140 to allow a removal of a cover from a vat located in the source fiducial location opening 132 or 134. The peel monitoring sensor 230 may be located behind the sealed window 124 that separates the sensor 230 from the sealable chamber 100. The peel monitoring sensor 230 may be a CCD camera or any other light sensor that is addressable or configurable through software or other suitable means to provide a total light signal from a predefined portion of your field of view.

[00104] In Figures 8A to 8D, the container bowl 530 is shown located in the fiducial location opening 132, which is obscured by the bowl 530 while the bowl 530 has its cover 520 removed or peeled off by the cover removal station 140. Use of coupling tool 142 and cover removal accessory 540 attached to cover 520 has already been described.

[00105] As shown in Figure 7, the charging system 1000 may comprise the peel monitoring light source 240 arranged to illuminate a portion of the rotary stage 130 proximate the coating removal station 140. The peel monitoring light source stripping 240 provides an appropriately high amount of illumination to ensure that its illumination strongly dominates any ambient light in the system 1000. In order to further ensure that the illumination of the light source 240 can be differentiated from the ambient light, the light source 240 may be of a selected wavelength or wavelength range. A suitable choice of device for light source 240 may be an infrared light-emitting diode. The light source 240 may be provided with an optical wavelength filter 242 that transmits only light of suitably differentiated infrared radiation. Light source 240 may illuminate the relevant portion of rotary stage 130 through sealed window separating light source 240 from sealable chamber 100. For clarity, sealed window separating light source 240 from sealable chamber 100 not shown in Figure 7.

[00106] Since adequate contrast is advantageous in monitoring the coating removal or “peeling” process, and since the rotating stage 130 may have a surface that exhibits an amount of reflectivity that may interfere with the work of the sensor. peel monitoring 230, the light source 240 and the peel monitoring sensor 230 may be arranged relative to each other in such a way as to ensure that light from the light source 240 that is directly reflected by the rotating stage 130 is not directed into towards the peel monitoring sensor 230. For this purpose, the peel monitoring sensor 230 may be arranged facing the portion of the rotary stage 130 proximate the coating removal station 140, but located in a position that is outside of any plane defined by any line perpendicular to the rotating stage 130 within the area of the rotating stage 130 illuminated by the source 240 and the trajectory of any light from the light source 240 to the point at which the perpendicular line intersects the illuminated surface of the rotating stage 130. However , it is also advantageous for the peel monitoring sensor 230 to have as close as possible a plan view of the illuminated area of the rotating stage 130 without experiencing direct reflection from the rotating stage 130.

[00107] In Figure 7, an exemplary placement of peel monitoring sensor 230 and light source 240 is determined. The portion of the rotating stage 130 proximal to the cover removal station 140 is illuminated by the light source 240 at a tilt angle, with the light source 240 disposed on the rear wall of the sealable chamber 100 in order to obtain the required angle. The peel monitoring sensor 230 is disposed on the upper wall 110 of the sealable chamber 100. As readily evident from Figure 7, light from the light source 240 will not be specularly reflected by the surface of the portion of the rotating stage 130 proximate the peeling station. cover removal 140. This allows light from the light source 240 to be diffusely reflected by the cover 520 of the vat 530, when it is removed from the vat 530 by the cover removal station 140, to dominate in the light received by the peel monitoring sensor 230.

[00108] Turning now to Figures 8A to 8D which represent a progression of stages in a cover removal 520 from the vat 530 by the cover removal station 140. In the present specific report, the phrase “monitored area” is used to describe the area 232 of Figures 8A to 8D that is illuminated by the light source 240 and monitored by the peel monitoring sensor 230. During peeling or removal of the coating 520 in the system 1000, the rotary stage 130 is rotated and therefore the area monitored 232 changes position in the rotary stage 130 in the process.

[00109] Other pharmaceutical loading systems may be arranged differently and may function differently with respect to the location of fiducial location openings for vats. For example, in such other systems the fiducial location openings may be stationary and the covers may be removed solely by manipulating an associated cover removal station. In still additional systems, the fiducial location openings can be moved linearly, rather than being rotated as in the case of system 1000. In the broader implementation of the monitoring and control system for removing covers from vats carrying pharmaceutical containers or closures, only the fact that the cover is, in some way, peeled from the tub and is attached to it is considered.

[00110] In Figures 8A to 8D, the bowl 530 has a substantially rectangular shape with four corners and the entire bowl 530 is airtight against the environment by cover 520 when the bowl 530 is initially placed in the fiducial location opening 132, which is obscured by bowl 530 in Figures 8A to 8D. Cover 520 has four corresponding corners. The first corner of the cover 520 to be peeled from the tub 530 is the corner that is shown furthest from the cover removal station 140 in Figure 8A. In an implementation of the roof removal monitoring and control system of this specific report the peeling of the first corner of the roof is not monitored.

[00111] Figure 8A shows the situation very briefly after peeling the next corner of the cover 520, which is in this embodiment the corner of the cover 520 that corresponds to the corner of the leftmost side of the bowl 530 in Figure 8A. In the case of system 1000, peeling of the first and second corners of the cover 520 is accomplished by rotating the rotary stage 130 while the first corner of the cover 520 is retained by the cover removal station 140 using the engagement tool 142 and the cover removal accessory 540, as described above in this specific report.

[00112] By properly choosing the exact location of a first peel monitoring zone 234 within the monitored area 232, proximate to the second corner of the vat 530 and which does not substantially overlap the container vat 530 immediately upon completion of the peeling of the cover 520 from the second corner of the bowl 530, the light signal or image brightness produced by the sensor 230 when the second corner of the cover 520 has been peeled off can be made to be very large, thereby allowing a sensitive measurement of whether or not the second corner has been peeled off successfully. This results from a generally white coating 520 that substantially covers the monitoring zone 234 at the time peeling is completed and that diffusely reflects light from the light source 240 toward the peeling monitoring sensor 230.

[00113] The term “peeling monitoring zone” is used in this specification to describe a range of positions that the system is configured to evaluate in determining a peeling situation. This may be an entire three-dimensional volume that has a base defined by, for example, dotted line 232 in Figure 8A and a vertex defined by sensor 230, which makes the peel monitoring zone 234 an oblique cone. As such cover 520, upon being peeled, is introduced into its oblique cone, the cover 520 is superimposed on the peel monitoring zone 230. A variety of other suitable zone dimensions may also be provided, such as a zone collimated cylindrical beam, a narrowly focused beam, or even a moving scanning beam. It should also be noted that, generally speaking, the base of the three-dimensional volume that constitutes the peel monitoring zone should not be restricted to a single plane, nor should it have a base that is a conical cut. The base may be a defined portion of a sensor field of view 230, and may be distributed across different physical surfaces within the charging system 1000. It may also be possible to restrict how far the detection zone extends above the base.

[00114] Capture of the signal or image from sensor 230 may be timed to coincide with the moment when the second corner peeling is completed. If sensor 230 is an imaging sensor, monitoring zone 234 can be selected by software within the image produced by sensor 230. If sensor 230 is a non-imaging sensor, then a simple absolute light signal measurement will serve the same purpose. purpose. In both deployments, the distinction between unpeeled and peeled can be made based on the total light signal received from the first corner peel monitoring zone 234. To differentiate a good peel from a poor peel, a “value of level” may be established for the absolute signal measured by the sensor 230 of the monitoring zone 234. If the sensor 230 is an imaging sensor, then the measurements may be, for example, but without limitation, an average over the image received from the monitoring zone 234. It should be noted that the method does not require extensive image management or perspective correction, nor any compensation for lens distortions and the like, as is often required in machine vision applications. And although it is contemplated herein that the method is to be performed in connection with executing software on controller 400 or other processor, the same may be implemented at least in part with dedicated hardware.

[00115] In Figure 8B the peeling of a third corner of cover 520 is shown, which is the rightmost corner of cover 520 in Figure 8A. In Figure 8B, the rotary stage 130 has been rotated many degrees clockwise with respect to Figure 8A, so as to peel off the third corner of the cover 520, which is shown in Figure 8B having been peeled off. As is the case with the second corner of the cover 520, through a suitable choice of the exact location of the peel monitoring zone 236, which is close to the third corner of the vat 530 and which does not substantially overlap the container vat 530 immediately after completion of the peeling of the cover 520 from the third corner of the vat 530, the diffusely reflected signal or image produced by sensor 230 when the third corner of the cover 520 has been peeled off may be very large, which thereby allows a sensitive measurement of the possibility whether or not the third corner has been successfully peeled. The method for determining the peeling quality of the third corner may proceed exactly as in the case of the second corner, with the exception that it is the reflected light from the peeling monitoring zone 236 that is used to make the determination. In the case of system 1000, peeling of the first, second and third corners of the cover 520 is by rotation of the rotary stage 130 while the first corner of the cover 520 is retained by the cover removal station 140 using the engagement tool 142 and cover removal accessory 540, as described above in the present specification.

[00116] Peeling the fourth and last corner of cover 520, as in Figures 8C and D, presents some different challenge. Unlike the second and third corners, the peel quality cannot be assessed exclusively at the base of the diffusely white-reflecting coating 520 that covers any peel monitoring zone near the vat 530, as this would actually be evidence that the peeling has not been completed. A slightly different approach is therefore followed. Again, a suitable peel monitoring zone is chosen, which is the zone 238 proximate to the fourth corner of the vat 530 and which substantially overlaps the vat 530 immediately after completion of peeling of the cover 520 from the fourth corner of the vat 530. Two measurements are produced from zone 238, namely, a measurement at the time of Figure 8C just before the cover 520 finally detaches from the bowl 530, and another as in Figure 8D after it has been unfastened by the rotation of the cover removal station 140. The first of the two measurements should have a high signal as a result of the coating 540 diffusely reflecting much of the light from the light source 240 toward the peel monitoring sensor 230, and the second measurement should be very low due to the absence of any white covering material that diffusely reflects from cover 520 in zone 238. In a general implementation of the monitoring and control system for removing cover from vats supporting closures or pharmaceutical containers, rotary stage 130 and cover removal station 140 may be moved sequentially or can be moved simultaneously.

[00117] Based on the above description, the method for aseptically loading pharmaceutical containers with a pharmaceutical fluid substance, described above through the flow chart in Figure 2 A, may further comprise, as in the flow chart in Figure 9: monitoring and controlling the removal of [2040] container bowl cover 520 of the at least one container bowl 530 by a method comprising: illuminating [2042] the portion 232 of the rotary stage 130 proximate the cover removal station 140 with light from the light source 240 ; measuring [2044] a light intensity of the light source 240 diffusely reflected from the peel monitoring zone 234, 236, 238 proximate to and not substantially overlapping at least one container vat 530 immediately after completion of the coating peel 520 from a corner of at least one vat 530 proximate to the peeling monitoring zone 234, 236, 238; evaluating [2046] a current situation of the peeling of the container vat cover 520 of the at least one vat 530 in a corner of the vat 530 close to the peeling monitoring zone 234, 236, 238; decide [2048] a next step in the peeling process based on the current peeling situation.

[00118] In the above description of the peeling process, the peeling monitoring zones were chosen to be close to the relevant corner that is peeled and substantially non-overlapping with the vat 530, and reflected light measurements are made immediately upon completion of peeling. of coverage 520 of the relevant corners of the bowl 530. It will be understood that, in some embodiments, measurements may be made at predetermined times after completion of peeling of the corresponding corners, and corresponding peel monitoring zones may be chosen to be at corresponding locations commensurately different proximate corresponding corners of the vat 530 and substantially non-overlapping with the vat 530 and yet in the illuminated portion of the stage 130.

[00119] In some embodiments, instead of the single peel monitor sensor 230 that is employed, a plurality of separate peel monitor sensors may be employed with a different sensor among a plurality of unique sensors for measuring the light reflected from each individual peel monitoring zone, e.g., peel monitoring zones 234, 236, and 238. In additional embodiments, a plurality of light sources may be employed, which allows a separate light source to serve as illumination for each corresponding corner of the bowl 530 is monitored for peeling. In still further embodiments, different lighting wavelengths can be employed so that different corners are monitored, and the sources and sensors matched correspondingly by wavelength or wavelength range.

[00120] The output of sensor 230 can be used in several ways. In one embodiment, the sensor may provide via software in controller 400 a signal that indicates the possibility that a corner has been successfully peeled. If this signal indicates successful peeling of a corner, the controller can cause the system to continue peeling the cover until the next capture step is performed and this process can continue until the cover is completely removed. If the sensor detects a failure to remove a corner, the controller can stop platform movement, issue an alert, and/or provide other action that will allow the condition to be inspected and/or remedied.

[00121] Evaluation [2045] may comprise comparing the light intensity of the measurement with [2044] a predetermined light intensity value. The predetermined light intensity value can be chosen such that if it is exceeded by the measured light intensity during measurement [2044], this represents a large presence of the vat cover 520 within the peel monitoring zone 234, 236, 238, which in turn is evidence of the vat cover 520 that was successfully removed from the corner of the vat 530 near the peel monitoring zone 234, 236, 238. Illumination [2042] with light from the light source 240 may be illuminating [2042] with infrared light from light source 240.

[00122] The predetermined light intensity value may be stored in the memory of the controller 400. The controller 400 may contain suitable software programming instructions which, when loaded into memory and executed by the processor, control the rotary action of the rotary stage 130, measurements by sensor 230 and any required rotary or vertical movements of the cover removal station 140 in a mutually dependent and synchronized manner. This allows measurement [2044] to be timed to occur immediately upon completion of peeling of the cover 520 from one corner of the at least one vat 530 proximate the peel monitoring zone 234, 236, 238. The second measurement associated with the fourth corner of the bowl 530 can similarly be timed to occur when the bowl cover 520 has been completely unattached from the bowl 530. An assessment of the peeling of the last corner of the bowl 530 is made based on the last measurement which returns to a light intensity that is less than a predetermined value associated with the peel monitoring zone 238. The sequence of high intensity diffusely reflected light followed by high intensity diffusely reflected light is evidence of peeling in the last corner that occurs respectively and in the cover 520 that has been completely unattached and removed from the peeling monitoring zone 238. With this approach above, the coating removal monitoring and control process can be completely automated.

[00123] The same cover removal station 140, light source 240, sensor 230, and peel monitoring zones 234, 236, 238 can be employed to also remove a cover from a container closure vat by means of using a method similar to that described above.

[00124] Although the apparatus and method for monitoring the removal of a cover from a vat has been described above, within the scope of a system employing the turntable comprising a simple fiducial location opening for retaining the vat in a predetermined fixed position , this represents nothing more than a non-limiting example of a suitable system comprising a platform having a fiducial source location framework. Generally speaking, the platform is not limited to a rotating stage. The platform may be a mobile platform and may be movable along any general path that permits removal of the cover by a suitable cover removal station. The source fiducial location structure may be any fiducial location structure that has the ability to retain the bowl in a predetermined fixed position, including those described with reference to Figures 3A, 3B, 4A and 5A.

[00125] In one example, the system may be adapted to monitor cover removal in an apparatus of the type described in the United States Patent Application Publications noted above U.S. 2017-0248626 and U.S. 2016-0251206 that provides an articulated arm to retain the tank during cover removal. Since there is no rotary stage 130 in this case, the monitored zone 232 will extend over another peel monitoring surface within the aseptic chamber, such as an upper surface of a pedestal. Furthermore, although it is presently preferred that the surface be a horizontal surface that is monitored from the top, it may also be possible, in some examples, to monitor the coating removal process from another vantage point, such as from top to bottom. The optical properties of the monitored zone or at least the peel monitoring zones 234, 236, 238 can be provided with suitable optical properties to intensify the monitoring process. This can be achieved in several ways, such as by selecting the material that defines the monitored zone or by applying a coating or other surface treatment to some or all of the monitored zones.

[00126] The system can also be reorganized in several ways. Instead of the top-down reflective measurement presented above, for example, a bottom-up transmission measurement can be performed by placing one or more light sources in one or more peel detection zones in the monitored zone, such as how to integrate them into the platform. The system then successfully detects peeling by seeking coverage to block light from light sources from reaching the sensor.

[00127] Another embodiment of a charging system according to the invention may be, in all respects, identical to the embodiments described above with reference to Figures 1A and 1B, with the exception of the vacuum capture system (or vacuum capture systems). vacuum) 150 or 160. Figures 3A and 3B show a portion of a charging system as described above. Figure 3B, in particular, focuses on the general area of one of the vacuum capture systems, by way of example, vacuum capture system 150. In this alternative embodiment, the vacuum capture system 150 is replaced by a vacuum capture system 150. 150' reconfigurable vacuum. The vacuum capture system 160 of Figures 1A and 1B may be replaced by a reconfigurable vacuum capture system 160' of the same arrangement as the vacuum capture system 150'. For clarity, the vacuum capture system 160' is not shown in Figure 3A or 3B. In other embodiments, a single reconfigurable vacuum capture system 150' may be employed to capture both in-container and closure-in-container clusters. The vacuum capture system 150' can access the container clusters and container closure clusters by rotating the rotary stage 130.

[00128] The vacuum capture system 150' comprises two rotating arms 154a' and 154b' which in turn comprise pluralities of suction cups 152a' and 152b'. The vacuum capture system 150' is arranged to capture clusters 500 of the containers 510 by means of suction cups 152a' and 152b'. The vacuum capture system 150' may also be arranged to capture clusters 600 of container closures 610 via suction cups 152a' and 152b'. As for the vacuum capture system 150, the vacuum capture system 150' may be raised and lowered to allow suction cups 152a' and 152b' to engage different groupings 600 of container closures 610 contained at different depths. inside the tank 630.

[00129] The suction cups 152a' and 152b' are arranged on the rotating arms 154a' and 154b' as pluralities of sets of linearly arranged suction cups 152a' and 152b', each set of linearly arranged suction cups 152a' and 152b ' which are disposed at an angle perpendicular to the longitudinal geometric axes of rotating arms 154a' and 154b'. This arrangement allows the rotating arms 154a' and 154b' to be rotated about their longitudinal geometric axes in order to orient different sets of linearly arranged suction cups 152a' and 152b' to engage different groupings 500 of the containers 510. This allows suction cup assemblies 152a' and 152b' to be individually selectable for use. Rotation of rotating arms 154a' and 154b' can be carried out manually. In other embodiments, rotation of the rotating arms 154a' and 154b' may occur by means of a suitable motorized unit incorporated in a vacuum capture system 150' and controlled by the controller 400 shown in Figure 1A.

[00130] By selecting different sets of linearly arranged suction cups 152a' and 152b' by rotating rotating arms 154a' and 154b', the sets of suction cups 152a' and 152b' can be arranged to engage the different container groupings 500 that carry containers 510 or container closure groupings 600 that carry container closures 610.

[00131] Figures 3A and 3B show vacuum capture system 150' as comprising two rotating arms, which are rotating arms 154a' and 154b'. In other embodiments, one or more arms may be employed, all embodiments sharing the concept of a selectable configuration of suction cups. On the other hand, the selection of the suction cup configuration in Figure 3A and Figure 3B occurs by rotating the arms 154a' and 154b' that carry the suction cups 152a' and 152b', the selection in other modalities can occur in a different basis of configuration, including, for example, without limitation, lateral translation of suction cup bearing arms in a plane parallel to the plane of rotation of rotary stage 130 in order to engage different sets of suction cups with groupings of container or container closure groupings. In Figures 3A and 3B, the suction cups are arranged in linear arrays. In other embodiments, nonlinear arrangements of suction cups may be employed.

[00132] Turning now to Figure 3B specifically, members 149 and 139 are considered in greater detail. In one embodiment, the reconfigurable interrupt member 149 is shown as having two different ends of which a first end may be selected for use by suitably rotating the configurable interrupt member 149 about the geometric axis of rotation of the interrupt member 141 to a predetermined set position. In the defined position, the reconfigurable interruption member 149 provides a sharp interruption to a proximal end of the container 530 against the selected end of the reconfigurable interruption member 149 along a direction parallel to the longitudinal geometric axes of rotating arms 154a' and 154b'. In this embodiment, the reconfigurable interrupt member 149 may be rotated through 180 degrees to dispose the second end of the reconfigurable interrupt member 149 to interrupt the container 530. The second end of the reconfigurable interrupt member 149 may be configured to interrupt the end of the container 530 to a point other than where the first end of the reconfigurable interruption member 149 interrupts the proximal end of the container 530.

[00133] The restraining member 139 is configured to push against a distal end of the container 530. Although different mechanisms are contemplated to ensure the pushing action of the restraining member 139, a particular suitable means is by providing the restraining member 139 with spring loading suitable for rotating about the geometric axis 143. With the above operation, the reconfigurable stopping member 149 and the restraining member 139 together allow the container 530 to be positioned to an exact location parallel to the longitudinal geometric axes of the rotating arms 154a' and 154b'. The particular exact location is selectable by selecting the appropriate end of the reconfigurable stopping member 149 to stop the container 530. This arrangement allows containers 530 of different dimensions parallel to the longitudinal geometric axes of the rotating arms 154a' and 154b' to be located in the exact predetermined locations with respect to suction cup assemblies 152a' and 152b*.

[00134] A particular set of suction cups 152a' and 152b' may be selected to be compatible with the selection of the particular end of the reconfigurable interruption member 149. In this way, the vacuum capture system 150' may be set at a configuration that ensures that a selected size of container 530 is precisely positioned to allow groupings of container 500 within container 530 to be engaged by specific sets of suction cups 152a' and 152b'. The vacuum capture system 150' is then reconfigurable to engage different sized groupings within different sized containers.

[00135] For the sake of clarity, the description above, as well as Figures 3A and 3B, show an arrangement that allows the exact positioning of containers 530 along only one dimension in the plane of rotation of the rotary stage 130, the dimension of the containers perpendicular to a dimension that is considered identical. In such an arrangement, the fiducial location openings 132 and 134 are sized to retain the containers 530 in the perpendicular dimension in the plane of rotation of the rotary stage 130.

[00136] In another embodiment, an additional reconfigurable stopping member and a restraining member may be added to the arrangement of Figure 3A and Figure 3B in order to address positioning of the container 530 in the perpendicular direction within the plane of rotation of the rotary stage. 130. In order to allow positioning of the container 530 in this perpendicular direction, the fiducial location openings 132 and 134 are not sized to restrict containers in any direction within the plane of rotation of the rotary stage 130.

[00137] In the embodiments described above, the reconfigurable interruption member 149 has been described as having two ends of which one is selected for use at any time by rotating a reconfigurable interruption member 149 about the geometric axis of rotation of the control member. interruption 141. In other embodiments, the reconfigurable interruption member 149 may be shaped or configured to have more than two interruption ends, the ends being selectable by suitably rotating the reconfigurable interruption member 149 about the geometric axis of rotation of the interrupt member 141. In an embodiment, in which the reconfigurable interrupt member has a very large number of interrupt ends, the reconfigurable interrupt member may take the shape of a cam, which represents a large plurality of possible interrupt ends which may be selected by rotating the reconfigurable interrupt member about a suitable geometric axis of rotation of the interrupt member.

[00138] In general, the system described with reference to Figures 3A and 3B comprises a reconfigurable fiducial nest positioning system. The reconfigurable fiducial nest positioning system comprises a movable platform comprising fiducial location opening 132, reconfigurable stop member 149 and restraint member 139. In the case of the system of Figures 3A and 3B, the movable platform is a rotary stage 130. As explained later, other mobile platforms are also contemplated to the extent that, for example, the bowl 530 positionally constrains and locates the clusters 500 within the bowl 530, any system that fiducially locates the bowl 530 also indirectly locates fiducial way the nest 500.

[00139] All of the various embodiments contemplated comprise a reconfigurable vacuum capture system that can be configured to engage suction cups thereof to corresponding areas in a pharmaceutical container nest. The containers in the container nest may be closed by corresponding container closures suspended in a container closure nest. The plate container closure nest surface may have a contour that leaves passages on the perimeter thereof for suction cups to pass through to engage the container nest. By way of example, in Figure 3a, passages 602 are shown on the perimeter of the closure nest 600. Alternatively or additionally, the container closure nest may have suitable openings in the flat interior thereof to serve as passages for the container closure nests to pass through. suction pass to engage the container nest. The contemplated vacuum capture systems are further configured and arranged to capture the combination of grouped containers and closures thereof by the container nest, as opposed to the closure nest.

[00140] In a general embodiment, a nest handling subsystem comprises a reconfigurable vacuum capture system for capturing container clusters and/or the container closure clusters may comprise one or more arms that carry a plurality of cup assemblies. suction. By reconfiguring the vacuum capture system, a set of suction cups can be selected from a plurality of sets of suction cups, the selected set of suction cups being prearranged to engage with a particular container nest. or container closure nest. Selection can be based on either the size or shape of the nest or each of them. The nest handling system may further comprise at least one pair of reconfigurable stopping members 149 and restraining member 139 disposed proximate the opposite ends of the fiducial location opening 132 for retaining the tub 530 containing container clusters 500 carrying containers 510 in order to engage with opposite ends of the bowl 530. Stopping and restraining members are arranged to position the bowl 530 in a predetermined position that ensures that the selected set of suction cups can engage with the container groupings and/or groupings of container closure.

[00141] Same as the case with opening 132, opening 134 of Figure 3A may also be served by at least one set of a reconfigurable stopping member, which is member 145 in this case, and a restraining member, which is member 135 in this case. The reconfigurable stopping member 145 and restraining member 135 function with respect to any bowl in the opening 134 in the same way that the reconfigurable stopping member 149 and the restraining member 139 function with respect to any tub in an opening 132.

[00142] The above various embodiments have been described in terms of Figure 1A to E and Figure 3A, and Figure 3B in which the vacuum capture system 150, 160 is described as part of pharmaceutical loading system 1000. However, the system of vacuum capture 150', 160' may also be employed in its own right on apparatus not limited to the loading system of Figure 1A to 1E, or, in fact, to loading systems in general. Some other exemplary applications include, without limitation, freeze-drying systems. The same can apply to suitable groupings of any objects arranged in a predetermined pattern. Furthermore, although the system 1000 of Figure 1A to Figure 1E employs the rotary stage 130, the reconfigurable vacuum capture system 150' may employ any suitable moving platform comprising suitable fiducially located openings.

[00143] The method described above with reference to Figure 2A and 2B will now be described in greater detail with reference to Figure 3A and Figure 3B. Providing at least one vacuum capture system as part of providing an apparatus charging step [2010] may comprise providing at least one reconfigurable vacuum capture system 150', the at least one reconfigurable vacuum capture system 150 ' comprising a plurality of suction cup assemblies 152a' and 152b'.

[00144] Providing an apparatus loading stage [2010] may comprise providing rotary stage 130 with target fiducial location opening 136 and at least two source fiducial location openings 132, 134, each source fiducial location opening has at least one pair of reconfigurable interrupt members 149 and one restraint member 139.

[00145] The transfer step [2020] may comprise operating at least one first reconfigurable stopping member 149 to stop the container bowl 530 at a predetermined container bowl position and operating at least one first restraining member 139 to restrict the container bowl 530 in the predetermined container bowl position.

[00146] The transfer step [2025] may comprise operating at least one second reconfigurable stopping member 145 to stop the container closure bowl 630 at a predetermined closure bowl position and operating at least one second restraining member 135 to restricting the container bowl 630 to the predetermined closure bowl position.

[00147] The step of operating [2050] the at least one vacuum capture system 150', 160' may comprise configuring the at least one reconfigurable vacuum capture system 150', 160' to select a first set of predetermined suction arranged to engage with container nest 500.

[00148] Operation [2070] of one of the at least one vacuum capture system 150', 160' may comprise configuring the at least one reconfigurable vacuum capture system 150', 160' to select a second predetermined set of suction cups arranged to engage with container closure nest 600.

[00149] The method may further comprise operating [2095] at least one vacuum capture system 150', 160' with the first predetermined set of suction cups selected to engage the container nest 500 and together remove the container nest 500 and the container closure nest 600 of the collision system 180.

[00150] In Figure 3A and Figure 3B, alternative embodiments of the arrangements of the vacuum capture systems 150 and 160 of Figure 1a are considered in the form of the vacuum capture systems 150' and 160'; and positioning arrangements associated with source openings 132 and 134 in the form of elements 135,145,139, and 149. Attention is now given to alternative embodiments for the arrangements around opening 136 of Figure 1A and Figure 3A. Figure 4A and the roughly view in Figure 4B show the system of Figure 3A with a different embodiment of the arrangement around the target opening 136. Although the cameras 210 and 220 of Figure 1A may be employed in combination with the controller 400 and rotation of the rotary stage 130 to position the nest 500 in the opening 136 and to position the nest 600 over the nest 500 in the opening 136, the adjustable target fiducial positioning system of Figure 4A and Figure 4B comprising rotary positioning elements 164a and 164b may be an alternative. or additionally employed to precisely position the groupings 600 and 500.

[00151] Typical industrial container clusters are not manufactured to a dimensional standard and, as a result, any system for loading and closing the clustered containers 510 must have a mechanism for accurately positioning differently sized clusters 500 that hold containers 510. With For this purpose, rotary positioning elements 164a and 164b may have different sets of paired positioning surfaces 167a, 167b and 163a, 163b that allow clusters 500 of specific dimensions to be precisely fitted between such paired positioning surfaces. In Figure 4B, the nest 500 fits so that the two opposite ends thereof in a first dimension touch each other facing surfaces 167a and 167b of the rotatable positioning elements 164a and 164b respectively. By mutually counter-rotating the elements 164a and 164b around the respective geometric axes 166a and 166b, it is possible to make the surfaces 167a and 167b face each other and can then allow precise positioning between them of a nest. of different length in the first dimension.

[00152] As is evident from Figure 4B, when the surfaces 167a and 167b are facing each other, the nest positioned suitably between them can be retained in a predetermined and precise vertical position resting on the surfaces 165a and 165b of the elements rotary positioning devices 164a and 164b respectively. When the surfaces 163a and 163b face each other, the alternative nest suitably positioned between them can be retained in a predetermined and precise vertical position by resting on the surfaces 161a and 161b of the rotatable positioning elements 164a and 164b respectively. Elements 164a and 164b can be manually rotated around geometric axes 166a and 166b respectively. In some embodiments, rotation of elements 164a and 164b may be done automatically by means of motorized units controlled by controller 400 and suitable control software. This control may be based on predetermined dimensional data in relation to the nest that is positioned between the surfaces of elements 164a and 164b. This may also be based on input data derived from imaging data obtained from cameras 210 and/or 220. Additionally, rotation may occur as the nest 500 is lowered into position so that the particular surfaces of the elements 164a and 164b intended to engage with opposite ends of the nest 500 along the first dimension can serve as a horizontal closing handle on the nest 500 as the surfaces rotate towards the position in which they face each other. In this embodiment, the horizontal positioning and vertical positioning of a nest between elements 164a and 164b are not mutually independent.

[00153] Another arrangement, as shown in Figure 4A and Figure 4B for the first dimension of the nest 500, can also be established for the second planar dimension of the nest 500 perpendicular to the first dimension. This allows any nest 500 placed in opening 136 to be accurately located at a predetermined location by choosing the setting of rotary positioning elements 164a and 164b.

[00154] Another embodiment of rotating positioning elements is shown in Figure 5A and Figure 5B. In contrast to the embodiment of Figure 4A and Figure 4B described immediately above, the horizontal positioning and vertical positioning of a nest between two mutually counter-rotating elements 164a' and 164b' in Figure 5A and Figure 5B are mutually independent positioning actions. This is achieved by employing, in each of the two mutually perpendicular planar dimensions treated in the immediately above embodiment, a pair of fixed opposing planar tabs 165a' and 165b' to position the nest 500 in the vertical dimension, and a pair of positioning elements swivels 164a' and 164b' to position the nest 500 in the first horizontal dimension. In this embodiment, each of the elements 164a' and 164b' comprise two rotating elements combined on axes 166a' and 166b' respectively to rotate in unison and in mutual alignment on either side of the flat tabs 165a' and 165b' within the projections 169a' and 169b' respectively. The sets of rotating elements 164a' and 164b', in addition to each being divided into two combined elements, serve to entrust the nest 500 to the horizontal dimension in the same manner as the rotating elements 164a and 164b in the embodiment of Figure 4A and Figure 4B described. immediately above.

[00155] Although elements 164a' and 164b' can be designed to have more complex shapes, a very simple implementation is shown in Figure 5A and Figure 5B in which surfaces 167a' of rotating elements 164a' and surfaces 167b' of rotating elements 164b' serve to position the nest 500 in the first horizontal dimension. By rotating the elements 164a' joined by an axis 166a' counterclockwise within the projection 169a' and rotating elements 164b' joined by the axis 166b' clockwise within the projection 169b', it can be made that the surfaces 163a' and 163b' face each other and thus a nest of different length in the first horizontal dimension can be positioned and located precisely between elements 164a' and 164b'.

[00156] The combined elements 164a' and 164b' can be manually rotated around the axes 166a' and 166b' respectively within the projections 169a' and 169b' respectively. In some embodiments, rotation of elements 164a and 164b may be done automatically by means of motorized units controlled by controller 400 and suitable control software. This control may be based on predetermined dimensional data in relation to the nest that is positioned between the surfaces of elements 164a and 164b. This may also be based on input data derived from imaging data obtained from cameras 210 and/or 220. Additionally, rotation may occur as the nest 500 is lowered into position so that the particular surfaces of the elements 164a and 164b intended to engage with opposite ends of the nest 500 along the first dimension can serve as a horizontal closing handle on the nest 500 as the surfaces rotate toward the position in which they face each other.

[00157] Figure 5A and Figure 5B show an additional set of mutually paired counter-rotating rotary positioning elements not numbered for clarity, similarly combined for elements 164a' and 164b' and arranged to accurately locate 500 independently in the vertical dimension and in a second plane nest dimension 500 perpendicular to the first dimension.

[00158] In a further aspect, described with reference to Figure 6, there is provided a method for loading nested pharmaceutical containers 510 with a pharmaceutical fluid substance, the method comprising: providing [6010] the loading system 1000 comprising chamber sterilizable 100 capable of maintaining an aseptic condition, the chamber 100 comprising charging station 170 and rotating stage plane 130 having target location structure 136, 164a, 164b, 164a', 164b'; transferring [6020] into the chamber at least one container well 530 sealed by container well cover 520 and containing the container nest 500 that holds a plurality of pharmaceutical containers 510; aseptically seal [6040] the chamber 100; establishing [6050] an aseptic condition within the chamber 100; transferring [6060] into the target location structure 136, 164a, 164b, 164a', 164b' container nest 500 that holds a plurality of pharmaceutical containers 510 so that the container nest 500 is held in place; and dispensing [6070] the pharmaceutical fluid substance into at least a portion of a plurality of pharmaceutical containers 510 by operating both the rotary stage 130 and the loading station 170. Operating the loading station 170 may include rotating the loading station 170. Dispensing of dispensing the pharmaceutical fluid substance may comprise dispensing the pharmaceutical fluid substance on an iterative and serial basis into containers 510.

[00159] The provision [6010] of the loading system 1000 may comprise providing loading apparatus comprising at least one cover removal station 140 within chamber 100 and wherein the transfer into the container vat destination location structure 530 comprises removing the container bowl cover 520 from the container bowl 530 by operating both the rotary stage 130 and the at least one cover removal station 140. Operating the at least one cover removal station 140 may comprise rotating the at least one station of cover removal 140. The provision [6010] of the loading system 1000 may comprise providing within the chamber 100 at least one cover removal station 140 having coupling tool 142, transferring [6020] to the chamber 100 at least one bowl of container 530 may comprise attaching to the container bowl 520 cover, cover removal accessory 540; and wherein operating the at least one cover removal station 140 comprises engaging the engagement tool 142 with the cover removal accessory 540.

[00160] The method may further comprise transferring [6030] into the chamber a container closure vat 630 sealed by a container closure vat cover and containing at least one container closure nest 600 that holds a plurality of container closures. pharmacists 610. The method may further comprise positioning [6080] one of at least one closure nest 600 to align closures 610 in the at least one closure nest 600 with corresponding containers 530 in the container nest 500; transferring [6090] nests 500,600 of aligned enclosures 610 and containers 510 to a collision station by rotating the rotary stage 130; and forcing [6100] the closures 610 into corresponding containers 510. The method may further include adjusting the vat locating structure 135,145 to accommodate a size of the closure nest vat 630. Positioning [6080] one of the at least one nest of closure 600 may comprise obtaining image information about the one of the at least one closure nest 600, and positioning the one of the at least one closure nest based on the image information. Positioning [6080] of one of at least one closure nest 600 may comprise: applying a vacuum to the suction cups 162, 152a, 152b, 152a', 152b'; lifting the container closure nest 600 with the suction cups; and operate the rotary stage 130.

[00161] Transferring [6020] into the target location opening container nest 500 may comprise: applying a vacuum to the suction cups; raising a container nest 500 with the suction cups; and operating the rotary stage 130. The method may further include selecting one of a plurality of sets of suction cups and wherein applying a vacuum to the suction cups is performed for the selected set of suction cups. Selection may include rotating one of a plurality of sets of suction cups into position. The method may additionally include target location structure 136, 164a, 164b, 164a', 164b' to accommodate a container nest size 500. Adjustment may be performed in two at least generally orthogonal directions. The method may further include adjusting the bowl location structure 139,149 to accommodate a size of the container bowl nest 530.

[00162] In a further aspect, a method is provided (see Figure 1G) for removing within a controlled environment enclosure a container cover from a sealed container, e.g., vat 530 or vat 630, the sealed container being sealed by the container cover, e.g., cover 520, the method comprising: providing the container in the controlled environment enclosure 100 with the cover 520 sealed to a sealing surface of a rim of the container to seal the contents of the container against decontamination, being that the cover 520 has cover removal accessory 540, decontaminate the container sealed in the controlled environment housing 100, engage the cover removal accessory 540 with the coupling tool 142 and remove the cover from the container using the coupling tool 142. The coupler can engage a cover removal accessory 540 with the fork-shaped coupling tool 142. The coupler can engage a ball-shaped accessory with the cover removal accessory 540.

[00163] Supply may include providing sterilized pharmaceutical containers 510 or closures 610 in the sealed container, e.g., vat 530 or 630, prior to decontamination. Securing may occur before the container is in the controlled environment housing 100. Decontamination of the sealed container in the controlled environment housing 100 may occur prior to removing the cover 520. Removing the cover 520 may include moving engagement tool 142 relative to the container 530. Removing cover 520 may include moving both container 530 and coupling tool 142. The method may further comprise attaching cover removal accessory 540 to cover 520 before providing container 530 into the controlled environment enclosure.

[00164] Although the present invention has been described to present an exemplary design, the present invention may be further modified within the spirit and scope of the present disclosure. This application is therefore intended to cover any variations, uses or adaptations of the invention using its general principles. Additionally, this application is intended to cover such departures from the present disclosure as covered by known or customary practice in the art to which the present invention relates.

Claims (10)

1. Method for loading nested pharmaceutical containers (510) with a pharmaceutical fluid substance, the method characterized by the fact that it comprises the steps of: providing (6010) a loading system (1000) comprising a sterilizable chamber (100) having capable of maintaining an aseptic condition, the chamber (100) comprising a charging station (170) and a flat rotary stage (130) having a target location structure (136, 164a, 164b, 164a', 164b'); transferring (6020) to the chamber (100) at least one container well (530) sealed by a container well cover (520) and containing a container nest (500) that supports a plurality of pharmaceutical containers (510) ; aseptically seal (6040) the chamber (100); establishing (6050) an aseptic condition within the chamber (100); transferring (6060) to the target location structure (136, 164a, 164b, 164a', 164b') the container nest (500) supporting the plurality of pharmaceutical containers (510), so that the container nest ( 500) is held in place; distributing (6070) the pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers (510) by operating both the rotary stage (130) and the loading station (170); transferring (6030) to the chamber (100) a container closure bowl (630) sealed by a container closure bowl cover and containing at least one container closure nest (600) that supports a plurality of container closures. pharmaceutical container (610); positioning (6080) one of the at least one closure nest (600) to align closures (610) in the at least one closure nest (600) with corresponding containers (510) in the container nest (500); transferring (6090) the aligned closure nests (610) and containers (510) to the pressing station by rotating the rotary stage (130); and forcing (6100) the closures (610) on the corresponding containers (510). 2. Method according to claim 1, characterized in that the step of operating the charging station (170) further comprises the step of rotating the charging station (170). 3. Method according to any one of claims 1 or 2, characterized by the fact that the step of distributing the fluid pharmaceutical substance comprises distributing the fluid pharmaceutical substance in an interactive and serial manner in the containers (510). 4. The method of any one of claims 1-3, characterized in that the step of providing (6010) a charging system (1000) further comprises the step of providing a charging apparatus comprising at least one cover removal station (140) within the chamber (100), and wherein the step of transferring (6060) to the target location structure (136, 164a, 164b, 164a', 164b') the container trough (530) further comprises removing the container bowl cover (520) from the container bowl (530) by operating both the rotary stage (170) and at least one cover removal station (140). 5. Method according to any one of claims 1 to 4, characterized in that the step of operating at least one cover removal station (140) further comprises the step of rotating at least one cover removal station (140). 6. Method according to claim 4, characterized by the fact that: the step of providing (6010) the loading system (1000) further comprises providing within the chamber (100) at least one cover removal station (140) with a coupling tool (142), the step of transferring (6020) to the chamber (100) at least one container bowl (530) further comprises attaching to the container bowl cover (520) a cover removal accessory ( 540); and wherein the step of operating the at least one cover removal station (140) further comprises engaging the engagement tool (142) with the cover removal accessory (540). 7. Method according to any one of claims 16, characterized in that it further comprises the steps of: transferring to the chamber (100) a container closure bowl (630) sealed by a container closure bowl cover ( 620), and contain at least one container closure nest (600) that supports a plurality of pharmaceutical container closures (610). 8. Method according to any one of claims 1 to 7, characterized in that the step of positioning (6080) one of the at least one closure nest (600) further comprises the steps of: obtaining image information about the one of at least one nest closure (600); and positioning the one of the at least one closure nest (600) based on the image information. 9. Method according to any one of claims 1 to 8, characterized in that the step of positioning (6080) one of the at least one closure nest (600) further comprises the steps of: applying a vacuum to the cups of suction; lift the container closure nest (600) with the suction cups; and operating the rotary stage (130). 10. Method according to any one of claims 1 to 9, characterized in that the step of transferring (6060) to the target location structure the container nest (500) further comprises the steps of: applying a vacuum to the suction cups; lift the container nest (500) with the suction cups; and operating the rotary stage (130).